Superior Anticancer and Antifungal Activities of New Sulfanyl-Substituted Niclosamide Derivatives

The approved anthelmintic salicylanilide drug niclosamide has shown promising anticancer and antimicrobial activities. In this study, new niclosamide derivatives with trifluoromethyl, trifluoromethylsulfanyl,
and pentafluorosulfanyl substituents replacing the nitro group of niclosamide
were prepared (including the ethanolamine salts of two promising salicylanilides) and tested for their
anticancer activities against esophageal adenocarcinoma (EAC) cells. In addition, antifungal activity
against a panel of Madurella mycetomatis strains, the most abundant causative agent of the neglected
tropical disease eumycetoma, was evaluated. The new compounds revealed higher activities against
EAC and fungal cells than the parent compound niclosamide. The ethanolamine salt 3a was the most
active compound against EAC cells (IC50 = 0.8–1.0 μM), and its anticancer effects were mediated
by the downregulation of anti-apoptotic proteins (BCL2 and MCL1) and by decreasing levels of
β-catenin and the phosphorylation of STAT3. The plausibility of binding to the latter factors was
confirmed by molecular docking. The compounds 2a and 2b showed high in vitro antifungal activity
against M. mycetomatis (IC50 = 0.2–0.3 μM) and were not toxic to Galleria mellonella larvae. Slight
improvements in the survival rate of G. mellonella larvae infected with M. mycetomatis were observed.
Thus, salicylanilides such as 2a and 3a can become new anticancer and antifungal drugs.